Project Summary More than 90% of cardiovascular diseases (CVD) and cognitive impairment/dementia occur in men and women >50 years of age. Changes in age demographics in the U.S. predict progressive increases in these disorders without effective, evidence-based interventions. The age-related increase in systolic blood pressure (SBP) is a major factor driving the increased risk of these disorders in later middle-aged and older (MA/O) adults. This increase in SBP is due primarily to stiffening of the large elastic arteries, as indicated by increased carotid-femoral pulse wave velocity (CFPWV), which reflects stiffening of the aorta. Aortic stiffening with aging is mediated by structural and functional (increased vascular smooth muscle tone) changes in the arterial wall stimulated by oxidative stress and chronic low-grade inflammation. New BP guidelines describe a casual (resting) SBP of 120-129 mmHg as ?elevated? and SBP of 130-139 mmHg as ?stage 1 hypertension?, as these levels account for much of the increased risk of CVD and other BP-influenced disorders of aging. Importantly, ~50% of adults age >50 have SBP within these ranges. The first-line treatment for lowering SBP in these ranges is lifestyle-based therapy. In this context, we have shown that caloric restriction (CR) reduces SBP and CFPWV in older mice and in overweight/obese MA/O humans, but adherence is poor and CR reduces muscle and bone mass. As a result, we have since shown that boosting NAD+ bioavailability to stimulate SIRT-1, a ?CR mimetic? approach, reduces CFPWV and oxidative stress in old mice, and we recently took the first step in translating these findings in a small pilot study of MA/O adults (n=24). We found that supplementation with nicotinamide riboside, a natural, commercially available precursor of NAD+ and novel CR mimetic, was well-tolerated and increased NAD+ bioavailability in the overall group, and reduced SBP (-8 mmHg) and CFPWV in a subgroup (n=13) with baseline SBP of 120-139 mmHg. Here we propose a randomized, placebo controlled, double-blind, single-site phase IIa clinical trial to assess the safety and efficacy of oral nicotinamide riboside (500 mg capsules 2x/day; NIAGEN; ChromaDex Inc.) for 3 months vs. placebo (n=59/group) for decreasing SBP and aortic stiffness in MA/O men and women (50-79 years) with SBP in the elevated/stage 1 hypertension (120-139 mmHg) range. We hypothesize that treatment will be safe and well-tolerated, and will reduce SBP and CFPWV, as related to increases in systemic NAD+ bioavailability and reductions in vasoconstrictor factors, oxidative stress and inflammation. Aim 1: To measure casual SBP (primary outcome) before/after nicotinamide riboside vs. placebo treatment; Aim 2: To measure 24-hour ambulatory SBP and CFPWV (secondary outcomes) before and after treatment; Aim 3: To determine the safety and tolerability of treatment with nicotinamide riboside vs. placebo; Aim 4: To measure systemic NAD+ and NAD+?related metabolite concentrations, as well as circulating markers of vasoconstriction factors, oxidative stress and inflammation before and after treatment.